We can’t read Emory neuroscientist Shannon Gourley’s papers on social isolation in adolescent mice, without thinking about how the COVID-19 pandemic is affecting children and teenagers. Much of the experimental work was completed before the pandemic began. Still, in the future, researchers will be studying the effects of the pandemic on children, in terms of depression and anxiety, or effects on relationships and education. They could look to neuroscience studies such as Gourley’s for insights into brain mechanisms.
In the brain, social isolation interferes with the pruning of dendritic spines, the structures that underly connections between neurons. One might think that more dendritic spines are good, but the brain is like a sculpture taking shape – the spines represent processes that are refined as humans and animals mature.
Mice with a history of social isolation have higher spine densities in regions of the brain relevant to decision-making, such as the prefrontal cortex, the Emory researchers found.
In a recently published review, Gourley and her co-authors, former graduate student Elizabeth Hinton and current MD/PhD Dan Li, say that more research is needed on whether non-social enrichment, such as frequent introduction of new toys, can compensate for or attenuate the effects of social isolation.
This research is part of an effort to view adolescent mental health problems, such as depression, obesity or substance abuse, through the prism of decision-making. The experiments distinguish between goal-oriented behaviors and habits. For humans, this might suggest choices about work/school, food, or maybe personal hygiene. But in a mouse context, this consists of having them poke their noses in places that will get them tasty food pellets, while they decode the information they have been given about what to expect.
Outcome devaluation: Animals are allowed to freely consume one of two types of pellet (grey), decreasing the value of that outcome. Contingency degradation: One action is reinforced as during training, while the other action is no longer linked to reinforcement and instead the pellet associated with that action is “for free”. Figures by Dan Li
Social isolation — for a month, the adolescent time period in rodents — weakens the ability of mice to display goal-oriented behavior, so that they can adjust their behavior based on updated cues. Mice isolated in adolescence are more likely to favor habit-like behaviors, even after they are returned to living with their peers. This is not the case for isolation during adulthood.
We should note that the Gourley lab’s experiments focus on female mice, because male mice of the same strain are aggressive and are routinely isolated. They performed one experiment with male mice to show that social isolation did not have the same behavioral effects on them.
The Gourley lab’s 2019 paper concludes: “Our findings suggest that adolescence is a critical period during which social experience optimizes one’s ability to seek and attain goals later in life. Age-typical dendritic spine elimination appears to be an essential factor, and in its absence, organisms may defer to habit-based behaviors.”
In the body, social isolation reduces levels of corticosterone (CORT), a stress hormone whose levels are normally elevated during adolescence. The elevated levels appear to be important for dendritic spine pruning. Giving mice a corticosterone antagonist during that time period could match the effects of social isolation on behavior.
“It’s probably overly simplistic to say CORT causes proper pruning,” Gourley says. “Instead, it’s more like physiologically typical CORT leads to proper pruning. Too much or too little is unwelcome.”
Corticosterone fluctuates according to a circadian rhythm – it peaks at the beginning of the dark phase, when rodents are active.
“Paradoxically, both a flattened CORT curve and high CORT levels are associated with stress-related mood disorders like PTSD,” she says. “We measured CORT when it should be high, so our low levels could suggest a flattening of the curve – or perhaps a negative feedback loop from high levels at other points in the cycle.”
Gourley’s lab has shown that fasudil, an inhibitor of the cytoskeletal regulatory enzyme ROCK, could reduce the proportion of dendrites with high spine densities when administered during social isolation. Fasudil could block the effects of social isolation on decision-making behavior, unlike the conventional SSRI antidepressant fluoxetine (Prozac).
Gourley’s lab has been studying fasudil for its antidepressant-like properties in adolescent mice. Fasudil has been approved for use in cerebral vasospasm in Japan and China, but is not approved in the United States or Europe. Fasudil was recently licensed by an American company, Woolsey Pharmaceuticals, which intends to repurpose it for neurodegenerative diseases.
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